PHASE-I EVALUATION OF RADIATION COMBINED WITH RECOMBINANT INTERFERON ALPHA-2A AND BCNU FOR PATIENTS WITH HIGH-GRADE GLIOMA

Purpose: A Phase I study to determine the safety, toxicity, and maximu m tolerated dose (MTD) of carmustine (BCNU) and interferon alpha-2a (I FN-a) when combined with radiation as initial therapy in high-grade gl ioma. Methods and Materials: Patients with newly diagnosed Grade 3 or 4 astrocytoma, oligoastrocytoma, or gliosarcoma were enrolled after su rgery. All received radiation therapy to the brain (64.8 Gy/36 fractio ns), combined with a single dose of BCNU (200 mg/m(2)) at the start of radiation. Chemotherapy after completing radiation consisted of BCNU 150 mg/m(2) once every 7 weeks, and IFN-a 12 x 10(6) units/m(2) subcut aneously Days 1-3 each week of a 7-week cycle. Subsequent dose modific ation was based on constitutional symptoms for IFN-a and on myelosuppr ession for BCNU. Results: Fifteen patients were entered on the study. Four were excluded because they did not receive IFN-a (3 refused treat ment and 1 patient left the study due to multiple medical problems). E leven were evaluable for toxicity and efficacy. Nonhematological toxic ity, mainly lethargy and flu-like symptoms, were dose-limiting for IFN -a. After the first 6 patients were treated per the initial protocol, the frequency of IFN-a administration was decreased to Days 1-3 on wee ks 1, 3, and 5 of the 7-week cycle for 5 additional patients. Lethargy , fever, chills, myalgias, alopecia, and anorexia occurred in all pati ents. Other toxicities included nausea and vomiting (91%), central-ner vous-system depression or mood changes (64%), headaches (55%), and ele vation of liver enzymes (36%). Grade 3-4 leukopenia occurred in 4 (45% ) of 11 patients, and Grade 3-4 thrombocytopenia in 3 (27%) of 11 pati ents. Due to myelosuppressive effects, BCNU dose was not escalated. Me dian survival of the cohort was 44 months. Objective responses occurre d in 5 (56%) of 9 patients and median duration of response was 33 mont hs. The MTD of this combination after radiation therapy is IFN-a 12 x 10(6) units/m(2) Days 1-3, on Weeks 1, 3, and 5 of a 7-week cycle and BCNU 150 mg/m(2) Day 1, every 7 weeks. Conclusions: Treatment with rad iation, IFN-a, and BCNU is feasible and effective in patients with hig h-grade gliomas, although constitutional symptoms from IFN-a are subst antial. (C) 1998 Elsevier Science Inc.